Antibody induced T cell mediated neonatal autoimmunity

我们最近对自身免疫性卵巢疾病（AOD）的研究已经积累了证据，表明抗原和环境因素在生命早期的刺激使遗传易感小鼠易患早发性和晚发性自身免疫性疾病，这可以通过CD4+CD2.5+调节性T细胞在生命早期的相对缺乏来解释。我们现在有了一个新的、引人注目的观察结果，进一步加强了这一范式。发现卵巢透明带3 (ZP3) B细胞表位（335-342）的自身抗体（autoAb）在新生小鼠中优先损伤卵巢，而在成年小鼠中保留卵巢。有趣的是，尽管卵巢疾病是由ZP3自身抗体引发的，但疾病的表达取决于新生儿体内T细胞的存在，并与新生儿自身T细胞对卵巢抗原的反应有关。此外，这种新生儿AOD的诱导是B细胞表位特异性的；因此，对第二个ZP3原生B细胞表位（171-180）的自身抗体是非致病性的。更令人兴奋的是，只有当autoAb在出生后5天内首次到达新生小鼠体内时，新生儿AOD才会发生。定理：母体自身抗体可引发新生儿致病性自身抗体反应和新生儿AOD；这种诱导是B细胞表位特异性的，并且只影响新生儿的mi_t，已知在古拉氏T细胞中是有定义的。我们现在提出以下实验方法来进一步研究这些新的和令人兴奋的观察。H_我们将验证新生儿AOD是由表位特异性自身抗体触发的假设，它与内源性Ag形成免疫复合物，诱导ZP3特异性致病性T细胞反应和长期自身免疫记忆。其次，我们将验证免疫复合物激活抗原呈递细胞依赖于其Fc受体的假设，这一事件是新生儿AOD诱导所必需的。第三，我们将验证新生小鼠CD4+ CD25+调节性T细胞缺乏解释新生小鼠发生自身免疫反应和疾病的倾向的假设。因此，该提案将解决自身免疫诱导和预防的基本机制，特别是新生儿自身免疫性疾病，包括系统性狼疮相关的先天性心脏传导阻滞。PERFORCE Si_ (S) (organizatiocnit y状态)大学弗吉尼亚CiaariottesvilteV,又关键人员 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED, Our recent studies on autoJmmune ovarian disease (AOD) have accrued evidence that stimulation by antigen and environmental factor early in life predisposes genetically-susceptible mice to early- and late-onset autoimmune disease, and this is explicable by the relative paucity of the CD4+CD2.5+ regulatory T cells present early in life. We have now made a new and striking observation that further strengthens the paradigm. Autoantibody (autoAb) to the ovarian zona pellncida 3 (ZP3) B cell epitope (335-342) was found to preferentially injure ovaries in neonatal mice while sparing ovaries of adult mice. Interestingly, although the ovarian disease is triggered by ZP3 autoAb, disease expression depends on the presence of T cells in the neonate, and is associated with de nero neonatal autoimmane T cell response to ovarian antigen. In addition, induction of this neonatal AOD is B cell epitope-specific; thus autoAb to a second ZP3 native B cell epitope (171-180) is non-pathogenic. Even more exciting, neonatal AOD develops only when the autoAb first reaches the neonatal mice in the first 5 days of life. Theorem, maternal autoAb can trigger in neonates pathogenic autoi_une T ¿¿11_sponse and neonatal AOD; the di_ _duction i_ B cell epito_snecific, and only imvacts neonatal mi_ _t are known to be defi¿i_ in _gulato_ T cells. We now propose the following experimental approaches to further investigate these new and exciting observations. H_ we will test the hypothesis that neonatal AOD is triggered by epitope-specific autoAb, which forms immune complexes with endogenous Ag, to induce ZP3 specific pathogenic T celt response and tong-term autoimmune memory. Second, we will test the hypothesis that activation of antigen presenting cells by immune complex is dependent on their Fc receptor, and this event is required for neonatal AOD induction. Third, we will test the hypothesis that CD4+ CD25+ regulatory T cell deficiency in neonatal mice explains the propensity of neonatal mice to develop autoimmune response and disease. This proposal will therefore address fundamental mechanisms responsible for autoimmune induction and prevention, and specifically, neonatal autoimmane diseases including systemic lupus-related congenital heart block. PERFORCE Si_(S) (organizatiocnit,y,state) Universityof Virginia CiaariottesvilteV, irginia KEY PERSONNEL ========================================Section End===========================================